Diabetic nephropathy (DN) is a common and devastating complication of Diabetes mellitus responsible for increased morbidity and mortality, loss of quality of live and rising costs. Current treatment options have shown only limited success. MicroRNAs (miRNAs) regulate gene expression on a post-transcriptional level, mediate many disease processes and are considered novel diagnostic and interventional candidate due to their biochemical structure. Therefore, the overall aim of this project is to define the role of miRNAs in DN. To identify candidate miRNAs that mediate progression of DN, we determined miRNA expression in glomeruli and tubule-interstitial compartments of patients with DN and normal glomerular filtration rate (GFR) and correlated miRNA expression with albuminuria, a risk factor for progression of DN. miR-21 was highly abundant and glomerular expression strongly correlated with albuminuria, whereas no correlation was detected with expression in tubulo-interstitial (TI) compartment. In murine models of glomerular injury loss of miR-21 was associated with increased proteinuria and podocyte apoptosis, consistent with findings in cancer models where miR-21 is considered oncogenic. In contrast, inhibition or loss of miR-21 ameliorates TI fibrosis after injury and does not regulate TEC-survival. In miR-21-deficient podocytes and tubular epithelial cells (TEC) unique transcriptomic responses to TGF-beta were detected, and inhibition or loss of miR-21 was associated with increased TGF-beta/Smad and ERK signaling activity in podocytes and glomeruli, but decreased activity in TEC and kidney cortex of diabetic mice. These findings suggest functions of miR-21 are dependent on cell-type. Furthermore, we determined that miR-34a expression is repressed by miR-21 and miR- 34a induces apoptosis in podocyte but has not effect on TEC survival, suggesting miR- 34 as a downstream mediator of cell-type-specific functions of miR-21. Cell-type specific function of miRNAs is further supported by different miRNA binding sites detected between primary neurons and podocytes using Photoactivatable-Ribonucleoside- Enhanced Crosslinking & Immunoprecipitation (PAR-CLIP) method to determine RNA transcripts incorporated into the RNA induced silencing complex (RISC). Therefore we hypothesize that the functions of miRNAs differentially expressed in DN and induced by cellular stress are not equivalent in all cell types and that those differences are at least partially reflected in the functions of transcripts of codig genes bound to RISC. We propose to test this for miR-21, which exhibits cell type- and context- specific functions and determine the role of miR-34 as a downstream mediator of cell- type specific functions of miR-21 in DN.